Dr. Laura Pinderski is a recently recruited Assistant Professor in the Department of Medicine/Division of Cardiology at the University of Alabama, Birmingham. During her cardiology fellowship, she obtained a Ph.D. in the laboratory of Dr. Judith Berliner within the Atherosclerosis Research Unit at UCLA. Her thesis work demonstrating that Interleukin-10 plays an important role in the regulation of the initiation of atherosclerotic lesions received the Irvine Page Award from the ATVB Council at the 2000 AHA Scientific Sessions. Dr. Pinderski is committed to an academic career as a cardiovascular physician-scientist. The Department of Medicine will ensure that Dr. Pinderski receives adequate support and protected time for this research proposal, per NIH guidelines. The career development program, mentor-derived guidance and structure will ensure that Dr. Pinderski reaches independent investigator status by the end of the requested three-year award period. This proposal will address the hypothesis that IL-10 regulates lesion progression and late remodeling of atherosclerosis, the leading cause of death in the Western world. LDL-receptor deficient mice will be used as a model of complex atherogenesis, and allowed to undergo atherosclerotic initiation under high fat/high cholesterol dietary stress. Once atherosclerotic initiation has been confirmed, IL-10 expression will be manipulated within specific cellular compartments of the immune system during atherosclerotic lesion progression. The specific aims are: 1) Analyze the effect of complete IL-10 deficiency on the progression of advanced atherosclerotic lesions; 2) Determine the extent to which alterations in lymphocyte IL-10 expression can impact progression of advanced atherosclerotic lesions; and 3) Determine the extent to which alteration of monocyte IL-10 expression can affect progression of advanced atherosclerotic lesions. These aims will be accomplished through the use of bone marrow transplantation and adoptive transfer of cellular subsets from genetically altered mice. We will evaluate cytokine production, lymphocyte activation and phenotype, monocyte activation and phenotype, total lesion quantity as well as specific lesion composition and character over time. As most human atherosclerosis is detected and treated after the stage of initiation, we anticipate the outcome of these studies will further our understanding of this devastating disease as well as potential treatment options.